Regulation of activity-dependent cerebral blood flow by astrocytes

大脑对能量的需求很高，但实际上没有储备能量的能力。因此，它高度依赖于与当地能源需求动态匹配的持续血液和营养流动。这是通过一种称为功能性充血(FH)的过程来实现的。FH是由活跃的神经元产生的分子信号导致的，这些信号转化为局部供血血管管腔直径的增加和血流量的增加。然而，调节FH及其空间协调的分子细胞间信号传递过程却知之甚少。我的长期愿景是全面了解负责将神经元能量需求转化为脑血管管腔直径和血流局部和远端协调变化的细胞间分子信号机制。我们和其他人提供了大量证据，证明被称为星形胶质细胞的脑细胞能够“监听”突触神经元的活动，并通过向局部血管系统发送血管扩张信号来增加血流量来做出反应。星形胶质细胞在FH的发生和空间传导中的作用将是我们短期计划目标的主要焦点。近期目标(~5年)是：1.表征由内皮NMDA受体介导的星形胶质细胞/内皮细胞信号转导；2.明确星形胶质细胞在血管运动极性代谢调控中的作用；3.表征星形胶质细胞在神经血管偶联中的异质性作用；4.在人类神经血管单位(NVU)方法学中建立研究星形胶质细胞-内皮偶联的模型，以确保高效传播并吸引和发展优秀的受训者。模型包括脑内皮细胞和星形胶质细胞培养、脑片穿透小动脉的双光子激光扫描显微镜(TPLSM)联合压力肌成像术、清醒动物的TPLSM以及人类神经血管偶联的模型。这些方法将利用创新和生理整合的技术和我的团队已经产生的新线索。我们将对星形胶质细胞如何影响内皮信号、血管扩张性神经血管偶联和功能性充血进行系统的机制研究--无论是在活动增强的局部部位，还是在由于传导血管扩张而导致的远端部位。FH机制描述了神经元如何根据需要进行喂养，这是大脑功能的基本原则。因此，我们的发现将对广大科学受众具有广泛的生物学和医学价值。我们的计划还将阐明神经血管耦合机制，以解释健康和疾病大脑中的功能磁共振数据。最后，我们在培训HQP方面拥有高影响力的论文、有竞争力的资金、奖项和领先的方法能力，这意味着我们的计划在吸引和培训高素质人才方面具有巨大的潜力。

The brain has a high energy demand but virtually no reserve energy capacity. Therefore, it is highly dependent on constant blood and nutrient flow matched dynamically with local energy demand. This is accomplished by a process called functional hyperemia (FH). FH results from creation of molecular signals from active neurons that translate to increases in the lumen diameter of local blood supply vessels and increased blood flow. However, the molecular cell to cell signaling processes that regulate FH and its spatial coordination are poorly understood. My long-term vision is to gain a comprehensive understanding of the intercellular molecular signaling mechanisms responsible for translating neuronal energy need to coordinated local and distal changes in brain vascular lumen diameter and blood flow. We and others have contributed to a wealth of evidence that brain cells called astrocytes are capable of "listening" to synaptic neuronal activity and reacting by sending vasodilatory signals to the local vasculature to increase blood flow. The role of astrocytes in genesis and spatial conduction of FH will be an overarching focus of our short term program objectives. Short term objectives (~5 years) are to: 1.Characterize astrocyte/endothelial signaling mediated by endothelial NMDA receptors 2.Define the role of astrocytes in metabolic control of vasomotor polarity 3.Characterize the role of regional astrocytic heterogeneity in neurovascular coupling 4.Develop models to study astrocyte-endothelial coupling in human neurovascular unit (NVU) Methodologies will address all objectives in a way that ensures high-impact dissemination and attracts and develops exceptional trainees. Models include brain endothelial cell and astrocyte cultures, combined pressure myography with two-photon laser scanning microscopy (TPLSM) of penetrating arterioles in brain slices, TPLSM in awake animals, and modeling of human neurovascular coupling. These approaches will leverage innovative and physiologically integrative technologies and novel leads already produced by my group. We will produce a systematic mechanistic investigation of how astrocytes influence endothelial signaling, vasodilatory neurovascular coupling and functional hyperemia - both in focal locations of enhanced activity and in distal sites due to conducted vasodilation. FH mechanisms describe how neurons are fed according to need as a basic tenet of brain function. Our findings will thus be of broad biological and medical interest to a wide scientific audience. Our program will also illuminate neurovascular coupling mechanisms central to interpretation of functional MRI data in healthy and diseased brain. Finally, our established track record of training HQP with high-impact papers, competitive funding, awards and leading edge of methodological capabilities means our program carries tremendous potential for attraction and training of high quality personnel.